Biology subjects

Verschut, V.

Publications and source records attributed to Verschut, V..

4 recordsLinked to original sources

bioRxiv2026

cGAS-STING drives alveolar epithelial cell dysfunction in cigarette smoke-induced lung injury

Chronic inflammation induced by cigarette smoke (CS) plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but its impact on lung epithelial progenitor function and regenerative capacity remains incompletely understood. Here, we combined in vivo and in vitro approaches to dissect how CS exposure and subsequent inflammatory insults shape epithelial repair dynamics. A 6-week whole-body CS exposure model in mice induced lung function impairment and altered gene expression profiles in alveolar epithelial cells, prominently activating interferon (IFN)-related pathways and the cGAS-STING axis. Alveolar epithelial cells from CS-exposed mice generated a similar number, but larger organoids with reduced alveolar differentiation compared to air-exposed mice. Notably, these cells obtained from CS-exposed mice displayed resistance to IFN{gamma}-induced suppression of organoid growth, contrasting with the strong inhibitory effect of IFN{gamma} observed in controls. This phenotype was recapitulated in a two-hit in vitro model using cigarette smoke extract (CSE), in which chronic CSE exposure impaired regeneration and differentiation while inducing resistance to IFN{gamma}. Gene expression and proteomic analyses revealed upregulation of Zbp1, Irf7, and other upstream IFN regulators, correlating negatively with alveolar differentiation potential. Inhibition of the cGAS-STING pathway with RU.521 partially rescued organoid formation, increased proliferation, and alveolar differentiation. Together, our data reveal that CS exposure alters the alveolar epithelial landscape, inducing a stress-adapted, IFN{gamma}-resistant state that compromises alveolar regeneration, with cGAS-STING activation as a key driver of early CS-associated alveolar type 2 cell dysfunction. These findings provide new insight into how chronic inflammation reshapes progenitor cell function during early lung injury.

Cell Biology↗

bioRxiv2024

Fibroblast-derived osteoglycin promotes epithelial cell repair

There is an urgent need for innovative pharmacological treatments targeting defective epithelial repair in chronic diseases, such as chronic obstructive pulmonary disease. The mesenchymal niche is a critical regulator in epithelial stem cell activation during repair. We hypothesized that secreted factors in this interaction are potent drug targets. Utilizing a cutting-edge proteomics-guided drug discovery strategy, we explored the lung fibroblast secretome to uncover impactful drug targets. Our lung organoid assays identified several regenerative ligands, with the secreted matrix protein osteoglycin (OGN) surprisingly showing the most profound effects. Transcriptomic analyses revealed that OGN enhances alveolar progenitor cell differentiation, boosts reactive oxygen species detoxification, reduces cellular senescence, and strengthens fibroblast-epithelial crosstalk. Critically, OGN expression was diminished in COPD patients and smoke-exposed mice. An active fragment of OGN, encompassing leucine-rich repeat regions 4-7, demonstrated regenerative potential akin to full-length OGN. This fragment significantly ameliorated elastase-induced lung injury precision-cut lung slices and improved lung function in vivo. These findings highlight lung fibroblast-derived OGN as a pivotal secreted protein for alveolar epithelial growth, positioning its active fragment as a promising therapeutic for epithelial repair in individuals with accelerated lung tissue damage.

pharmacology and toxicology↗

bioRxiv2021

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here we utilized a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors of which we screened the function in lung organoids. We found several drug targets with regenerative potential of which EP and IP prostanoid receptor ligands had the most significant therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we discovered by using scRNA-sequencing analysis that circadian clock and cell cycle/apoptosis signaling pathways were enriched in alveolar epithelial progenitor cells in COPD patients and in a relevant model of COPD, which was prevented by PGE2 or PGI2 mimetics. Conclusively, specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

pharmacology and toxicology↗

bioRxiv2020

The Streptomyces volatile 3-octanone alters auxin/cytokinin and growth in Arabidopsis thaliana via the gene family KISS ME DEADLY

Plants enhance their growth in the presence of particular soil bacteria due to volatile compounds affecting the homeostasis of plant growth hormones. However, the mechanisms of volatile compound signaling and plant perception has been unclear. This study identifies the bioactive volatile 3-octanone as a plant growth stimulating volatile, constitutively emitted by the soil bacterium Streptomyces coelicolor grown on a rich medium. When 3-octanone is applied to developing Arabidopsis thaliana seedlings, a family-wide induction of the Kelch-repeat F-box genes known as KISS ME DEADLY (KMD) subsequently alters auxin/cytokinin homeostasis to promote the growth of lateral roots and inhibit the primary root. Loss of function of the KMD family or other alterations of auxin/cytokinin homeostasis suppresses the volatile-induced growth response. This reveals a function of KMDs in the pathway of microbial volatile perception and plant growth responses. Significance StatementVolatiles from soil microbes are profound stimulators of plant growth. This work identifies for the first time a plant hormone signaling regulator, the gene family KISS ME DEADLY (KMD), to be an early essential step in plant growth promotion by a soil bacterial volatile, 3-octanone. The KMD-regulated gene network alters the tissue sensitivity balance for the growth hormones auxin and cytokinin, modifying root growth rate and architecture. Previously, the Kelch repeat F-box gene family of KMDs have been shown to be important down-regulators of both positive cytokinin signaling and phenylpropanoid biosynthesis, but upstream cues were unknown. This report places the KMD family regulation of plant growth and defense into its biotic context.

plant biology↗